ORGANIC LETTERS
Short Syntheses of (±)-δ-Araneosene and Humulene Utilizing a Combination of Four-Component Assembly and Palladium-Mediated Cyclization
2002 Vol. 4, No. 14 2441-2443
Tao Hu and E. J. Corey* Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street, Cambridge, Massachusetts 02138
[email protected] Received May 17, 2002
ABSTRACT
The four components shown are assembled in two steps, and the product is converted to araneosene by a short sequence.
The development of simple yet effective syntheses of multiprenyl natural products containing rings in the 9-11 size range continues to present a challenge, especially as more complex members of this class, such as the dollabellane group, are discovered.1 The research that is described herein originated from methodology developed for the synthesis of the pentacyclic marine natural product antheliolide A,2 which involved the rapid multicomponent coupling of prenyl units3 and facile Pd-mediated ring closure.4 Specifically, this paper describes the incorporation of these operations into new and effective syntheses of (()-δ-araneosene and (1) For a review, see: Rodriquez, A. D.; Gonzalez, E.; Ramirez, C. Tetrahedron 1998, 54, 11683. (2) (a) Green, D.; Carmely, S.; Benayahu, Y.; Kashman, Y. Tetrahedron Lett. 1988, 29, 1605. (b) Smith, A. B., III; Carrol, P. J.; Kashman, Y.; Green, D. Tetrahedron Lett. 1989, 30, 3363. (3) (a) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765. (b) Corey, E. J.; Lin, S.; Luo, G. Tetrahedron Lett. 1997, 38, 5771. (4) See: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b) Godleski, S. A. Nucleophiles with Allyl-Metal Complexes. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Chapter 3.3. (c) Trost, B. M.; Brickner, S. J. J. Am. Chem. Soc. 1983, 105, 568. (d) Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143. 10.1021/ol026205p CCC: $22.00 Published on Web 06/18/2002
© 2002 American Chemical Society
humulene, each of which contains an eleven-membered ring.
The synthesis of (()-δ-araneosene (1) is outlined in Scheme 1. The first synthesis of δ-araneosene was reported by Mehta and co-workers.5 A second synthesis was reported by Jenny and Borschberg.6 In the first step of our synthesis of 1, methyl tert-butyldimethylsilyl ketone was treated with (5) (a) Mehta, G. Pure Appl. Chem. 1990, 62, 1263. (b) Mehta, G.; Krishnamurthy, N.; Karra, S. R. J. Am. Chem. Soc. 1991, 113, 5765. (c) Mehta, G.; Karra, S. R.; Krishnamurthy, N. Tetrahedron Lett. 1994, 35, 2761. (6) Jenny, L.; Borschberg, H.-J. HelV. Chim. Acta 1995, 78, 715.
Scheme 1.
Synthesis of (()-δ-Araneosene
2-propenyllithium in ether and then with 2-isopropylallyl bromide in THF to give the (Z)-enolsilyl ether 2 (82%). The sequence of reactions that leads to 2 includes (1) carbonyl addition of 2-propenyllithium, (2) Brook rearrangement of Si from C to O, and (3) allylation of the resulting allylic lithium reagent.3 The silyl ether 2 was then transformed using (Me2N)3S+Me3SiF2- (TAS-F)7 into the corresponding TAS enolate, which was alkylated with bromide 38 to form the methyl ketone 4 (90%). Thus, all carbons of δ-araneosene were assembled from four readily available components in just two steps in ca. 73% yield. We see no reason the synthesis of 4 cannot be carried out without isolation of 2, thereby allowing a direct four-component synthesis of 4. Conversion of methyl ketone 4 into the allylic carbonate/ silyl ether 5 was effected in >99% yield using diisopropylethylamine and trimethylsilyl triflate in CH2Cl2 solution at (7) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc. 1980, 102, 1223. (b) Noyori, R.; Nishida, I.; Sakata, J. Tetrahedron Lett. 1980, 21, 2085. (8) For method of preparation, see Supporting Information. 2442
0 °C. Treatment of the allylic carbonate/silyl ether 5 with 10 mol % of Pd-dibenzylidene-acetone complex and bisdiphenylphosphinoferrocene (dppf) in THF at reflux for 1 h effected ring closure to form the 11-membered ketone 9 in 40-48% yield.9,10 The ketone 9 could also be prepared in somewhat higher yield (ca. 65%) by a longer alternative route through the intermediates 6, 7, and 8.5,11 Selective ozonolysis of 9 (ca. 0.8 equiv of O3) afforded the diketone 10, which was transformed by McMurry cyclization12 in 90% yield into (()-δ-araneosene. (9) To the best of our knowledge, the Pd(0)-catalyzed intramolecular allylation using silyl enol ether with allylic carbonate has not been documented before. For an intermolecular version of this type of coupling reaction, see: (a) Tsuji, J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 1325. (b) Tsuji, J.; Takahashi, K.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 4783. (10) The use of the chelating phosphine ligand dppf retarded β-hydrogen elimination (which gives acyclic diene) relative to ring closure; see (a) Hartwig, J. F.; Driver, M. S. J. Am. Chem. Soc. 1996, 118, 7217. (b) Hartwig, J. F.; Hamann, B. J. Am. Chem. Soc. 1997, 119, 12382. (11) For the conversion of 8 to 9, see: Corey, E. J.; Chaykowsky, M. J. Am. Chem. Soc. 1965, 87, 1345. Org. Lett., Vol. 4, No. 14, 2002
Scheme 2.
Synthesis of Humulene
The synthesis of humulene (11) was carried out by an approach paralleling that used for araneosene (1), as outlined in Scheme 2. Alkylation of the TBS enol ether of methyl isopropyl ketone13 by 3 afforded the keto carbonate 12 (92%), which could be converted cleanly into the corresponding TMS enol ether 13. Palladium-mediated cyclization of 13, as described above for the conversion 5 f 9, directly generated the required cycloundecadienone 14 in ca. 50% yield. This same compound was produced in ca. 65% yield from 13 by a longer process analogous to the sequence 5 f 8 f 9. Reduction of ketone 14 to the corresponding secondary alcohol by gradual addition of isopropyl alcohol (12) (a) McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977, 42, 2655. (b) McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989, 54, 3748. (c) McMurry, J. E. Chem. ReV. 1989, 89, 1513. (13) (a) Ohkata, K.; Mase, M.; Akiba, K. J. Chem. Soc., Chem. Commun. 1987, 1727. (b) This silyl enol ether could also be prepared from methyl tert-butyldimethylsilyl ketone and 2-propenyllithium followed by aqueous quench (84% yield) in a manner analogous to the preparation of 2 (Scheme 1). (14) (a) Corey, E. J.; Hamanaka, E. J. Am. Chem. Soc. 1967, 89, 2758. (b) Vig, O. P.; Ram, B.; Atwal, K. S.; Bari, S. S. Ind. J. Chem. 1976, 14B, 855. (c) Kitagawa, Y.; Itoh, A.; Hashimoto, S.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3864. (d) McMurry, J. E.; Matz, J. R. Tetrahedron Lett. 1982, 23, 2723. (e) Takahashi, T.; Kitamura, K.; Tsuji, J. Tetrahedron Lett. 1983, 24, 4695. (f) Corey, E. J.; Daigneault, S.; Dixon, B. R. Tetrahedron Lett. 1993, 34, 3675.
Org. Lett., Vol. 4, No. 14, 2002
to a well stirred suspension of sodium sand and 14 in toluene at 0 °C proceeded quantitatively. Reaction of this alcohol with methanesulfonyl chloride and triethylamine in CH2Cl2 at -35 °C for 30 min and -20 °C for 30 min gave the mesylate 15 (94% overall from 14). Elimination of methanesulfonate from 15 occurred upon stirring with silica gel in CH2Cl2 at 23 °C for 6 h to produce pure humulene (11), identical in all respects with an authentic sample. Of the several reported syntheses of humulene described, this is the simplest and most efficient.14 The syntheses of (()-δ-araneosene and humulene disclosed herein are noteworthy for the simplicity of the C-C bond constructions and cyclization steps, which we believe will prove advantageous in the synthesis of related polyterpenoids. Acknowledgment. We are grateful to Schering Plough for a Fellowship to T.H. Supporting Information Available: Experimental procedures for the reaction sequences outlined in Schemes 1 and 2, complete with physical and spectroscopic data for each intermediate. This material is available free of charge via the Internet at http://pubs.acs.org. OL026205P
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